Alzheimer's disease (AD) is a neurodegenerative disease affecting the elderly, which results in progressive impairment of memory, language skills and severe behavioral deficits. Hallmarks of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain and other regions of the brain important for memory and cognition. Other hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau and accumulation of amyloid β peptide (Aβ). Aβ is a 39-43 amino acid peptide produced in the brain by proteolytic processing of β-amyloid precursor protein (APP) by the β-amyloid cleaving enzyme (BACE) and gamma secretase which leads to accumulation of Aβ in the brain, where Aβ 1-40 and 1-42 are the principal aggregate-forming species of Aβ.
Schizophrenia is a debilitating psychiatric disorder characterized by a combination of negative (blunted affect, withdrawal, anhedonia) and positive (paranoia, hallucinations, delusions) symptoms, as well as marked cognitive deficits. While schizophrenia remains an idiopathic disorder, it appears to be produced by a complex interaction of biological, environmental, and genetic factors. Over 40 years ago it was found that phencyclidine (PCP) induces a psychotic state in humans that is very similar to that observed in schizophrenic patients. The finding that the main mode of action of PCP is that of a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptor stimulated a series of studies that have led to the development of the NMDA receptor hypofunction model of schizophrenia. Besides schizophrenia, dysfunction of glutamatergic pathways has been implicated in a number of disease states in the human central nervous system (CNS) including cognitive deficits, dementias, Parkinson's disease, Alzheimer's disease, and bipolar disorder.
NMDA receptor function can be modulated by activation of G-protein-coupled receptors (GPCRs) that are known to physically and/or functionally interact with the NMDA receptor. The NMDA receptor hypofunction hypothesis is a proposal to explain the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents, either directly by action on modulatory sites on the NMDA receptor (e.g., the glycine co-agonist binding site) or indirectly by activation of GPCRs known to potentiate NMDA receptor function (e.g., the M1 AChR), has the potential to ameliorate the symptoms of schizophrenia. In both preclinical and in clinical studies, Xanomeline, an M1/M4 preferring orthosteric agonist has proved efficacious with regard to positive, negative and cognitive symptoms, indicating that M1 activation is a reasonable approach to the treatment of schizophrenia. More recently, the selective M1 allosteric agonist TBPB demonstrated efficacy in multiple preclinical models of schizophrenia.
Positive allosteric modulators are compounds that bind to a target, such as a receptor, and can enhance the affinity or efficacy of an orthosteric agonist. For example, a selective muscarinic M1 positive allosteric modulator would preferentially bind to the muscarinic M1 receptor which would result in an increased affinity at that receptor for acetylcholine (ACh), the endogenous agonist for the muscarinic M1 receptor, or an increase in the efficacy induced by ACh. In some systems, the compound may also have an intrinsic activity to activate the receptor in the absence of orthosteric ligand. As another example, a dual M1/M4 positive allosteric modulator would induce a potentiating effect at both the M1 and M4 muscarinic receptors, but not necessarily to an identical extent at both receptors. Positive allosteric modulation (potentiation), therefore, can be an attractive mechanism for enhancing appropriate physiological receptor activation.
Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or the muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist acetylcholine (ACh). Acetylcholinesterase inhibitors, which inhibit the hydrolysis of ACh, have been approved in the United States for use in the palliative, but not disease-modifying, treatment of the cognitive deficits in AD patients. An alternative approach to pharmacologically increase the effects of ACh could be accomplished through the use of positive allosteric modulators, either alone or possibly in combination with other mAChR agonists. mAChRs are widely expressed throughout the body. The mAChRs are members of the family A GPCRs and include five subtypes, designated M1-M5. M1, M3 and M5 mainly couple to Gq and activate phospholipase C whereas M2 and M4 mainly couple to Gi/o and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system where they are prevalent and differentially expressed. M1-M5 mAChRs have varying roles in cognitive, sensory, motor, and autonomic functions. Activation of various muscarinic receptors, particularly the M1 subtype, has been proposed as a mechanism to enhance cognition in disorders such as AD. Thus, without wishing to be bound by theory, it is believed that selective positive allosteric modulators of mAChR subtypes that regulate processes involved in cognitive function could prove superior to AChE inhibitors for treatment of AD and related disorders as it is postulated that these compounds would exhibit improved selectivity for specific mAChRs
Evidence suggests that the most prominent adverse effects of AChE inhibitors and other cholinergic agents are mediated by activation of peripheral M2 and M3 mAChRs and include bradycardia, GI distress, excessive salivation, and sweating. In contrast, M1 has been viewed as the most likely subtype for mediating the effects on cognition, attention mechanisms, and sensory processing. Because of this, considerable effort has been focused on developing selective M1 agonists and positive allosteric modulators for the treatment of AD. Unfortunately, these efforts have been largely unsuccessful because of an inability to develop compounds that are highly selective for the M1 mAChR. Because of this, mAChR agonists that have been tested in clinical studies induce the same adverse effects of AChE inhibitors by activation of peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and to further explore the therapeutic utility of mACh receptors in AD and other disorders, it is be important to develop compounds that are highly selective positive allosteric modulators of M1 and other individual mAChR subtypes.
Previous attempts to develop activators that are highly selective for individual mAChR subtypes have failed because of the high conservation of the orthosteric ACh binding site. To circumvent problems associated with targeting the highly conserved orthosteric ACh site, a number of groups have shifted their focus to developing compounds that act at allosteric sites on mAChRs that are removed from the orthosteric site and are less highly conserved. This approach is proving to be successful in developing selective ligands for multiple GPCR subtypes. In the case of mAChRs, a major goal has been to develop allosteric ligands that selectively increase activity of M1 or other mAChR subtypes. Allosteric activators can include allosteric agonists, that act at a site removed from the orthosteric site to directly activate the receptor in the absence of ACh as well as positive allosteric modulators (PAMs), which do not activate the receptor directly but potentiate activation of the receptor by the endogenous orthosteric agonist ACh. Also, it is possible for a single molecule to have both allosteric potentiator and allosteric agonist activity.
Phase III trials have shown that orthosteric mAChR activators can have efficacy in improving cognitive performance in AD patients. Moreover, data indicate that administration of M1 activators decreases behavioral disturbances, including delusions, hallucinations, outbursts, and other symptoms in patients suffering from neurodegenerative diseases such as Alzheimer's disease. However, dose limiting adverse effects that may be due to lack of M1 mAChR selectivity led to failed launches of previous M1 agonists. In some cases, evidence suggests that mAChR activation also has the potential to be disease-modifying in that these agents may lower Aβ in AD patients.
Interestingly, data obtained with a number of M1-selective allosteric agonists and positive allosteric modulators suggest that selective activation of M1 may provide a novel approach for both symptomatic and disease modifying the treatment of Alzheimer's disease. For example, 1-[1′-(2-methylbenzyl)-1,4′-bipiperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (TBPB), a M1-selective allosteric agonist, was found to display effects on the processing of APP toward the non-amyloidogenic pathway and decrease Aβ 1-40 and 1-42 production in vitro (Jones, C. K., et al. (2008) J. Neurosci 28:10422-10433). The M1 positive allosteric modulators sodium 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (BQCA) and 2-((1-(5-bromo-2-fluorobenzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide (ML169) have been shown to shifted APP processing towards a non-amyloidogenic pathway (respectively, Shirey, J. K., et al. (2009) J. Neuorsci. 29:14271-14286; and Reid, P. R., et al. (2011) Bioorg. Med. Chem. Lett. 21:2697-2701). More recently, two new M1 positive allosteric modulators (1-((4,6-difluoro-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)methanamide and 1-((4,6-difluoro-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)methanamide) have been shown to potentiate CCh mediated APP processing (Tarr, J. C., et al. ACS Chem. Neurosci. (2012) 3:884-895).
Despite advances in muscarinic receptor (mAChR) research, there is still a scarcity of compounds that are potent, efficacious, and selective positive allosteric modulators of the M1 mAChR that are also effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity, or other neurologic diseases in which the muscarinic M1 receptor may be involved. These needs and other needs are addressed by the present invention.